Signal transduction is the general process by which cells respond to extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.) through a cascade of biochemical reactions that begins with the binding of the signal molecule to a cell membrane receptor and ends with the activation of an intracellular target molecule. Intermediate steps in this process involve the activation of various cytoplasmic proteins by phosphorylation via protein kinases and the eventual translocation of some of these activated proteins to the cell nucleus where the transcription of specific genes is triggered. The signal transduction process regulates all types of cell functions including cell proliferation, differentiation, and gene transcription.
Cytokines are a specific class of extracellular signal molecules that control growth, differentiation, and various functions of hemopoietic cells and immune cells. Cytokines include the interleukins (ILs), colony-stimulating factors (G-CSF and GM-CFS), erythropoietin (EPO), and various growth factors (EGF, PDGF, TGF, and FGF; Callard, R. and Gearing, A. (1994) The Cytokine Facts Book, pp 2-6, Academic Press, San Diego, Calif.).
Many of the cytokine receptors, including those for the growth factors EGF, PDGF, and FGF, contain intrinsic protein kinase activities. The binding of cytokine to the receptor, triggers the autophosphorylation of a tyrosine residue on the receptor. It is believed that these phosphorylated sites are recognition sites for the binding of other cytoplasmic signaling proteins in the signaling pathway that eventually links the initial receptor activation at the cell surface to the activation of a specific intracellular target molecule. These signaling proteins contain a common domain, a src homology 2 (SH2) domain, that is a recognition and binding site for the phosphotyrosine residue. SH2 domains are found in a variety of signaling molecules and oncogenic proteins such as phospholipase C-.gamma., Ras GTP-ase activating protein, and GRB2 (Lowenstein, E. J. et al. (1992) Cell 70:431-42).
Recently an SH2-containing protein was discovered that is induced by a subset of cytokines including IL-2, IL-3, GM-CSF, and EPO (Yoshimura, A. et al. (1995) EMBO Journal 14:2816-26). CIS (cytokine inducible SH2-containing protein) is a 257 amino acid protein containing a single SH2 domain in the middle of the molecule. CISbinds to the tyrosine-phosphorylated residues in the B chain of IL-3 receptor and in the EPO receptor.
Expression of CIS in hemopoietic cells transformed with the gene encoding CIS resulted in a marked suppression of cell growth (.about.50%). Yoshimura et al. (supra) interpret such suppression to suggest that CIS is a negative regulator of cell growth. The authors suggest that there are two possible mechanisms for this suppression. First, that CIS may operate as an adaptor protein for an as yet unidentified signal pathway which causes growth inhibition, and second, that CIS masks phosphotyrosine residues of activated receptors to prevent the binding of other signaling proteins. A third possibility is that binding of CIS to the activated receptor may trigger proteolytic breakdown of the receptor.
Research suggests that defects or alterations in the activity of signaling proteins such as CIS have implications for various proliferative disorders and diseases such as cancer. Loss of, or rearrangement of, the putative human gene encoding CIS is associated with renal cell carcinomas and lung cancer. This indicates that CIS may function as a tumor suppressor gene (Yoshimura et al., supra). Consistent with this possibility is the fact that CIS is expressed in a variety of tissues in addition to hematopoietic cells, including kidney, lung, liver, stomach, and heart.
The discovery of a new cytokine inducible regulatory protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and immune disorders.